Articular cartilage is a viscoelastic tissue essential for the absorption of shocks and distribution of loads. Because of its non-vascularized, non-innervated and sparsely cell populated nature, this tissue displays poor regenerative capacity. Recently, growth factor therapy has emerged as a novel strategy for enhancing chondrogenic differentiation and repairing functional cartilage. The heparan sulfate binding growth factor (HBGF) bone morphogenetic protein 2 (BMP2), which plays a critical role in the establishment of normal cartilage during development, also was found to enhance the differentiated phenotype of mesenchymal stem cells in culture. In addition, several studies indicate that BMP2 expression is elevated in damaged and/or mechanically-challenged cartilage during the early stages of osteoarthritis (OA). This increase in BMP2 levels is believed to enhance reparative processes and reactivate morphogenetic pathways including synthesis of extracellular matrix (ECM) components. During disease progression, the weakened synthetic machinery of chondrocytes eventually becomes unable to compensate for the degradation of ECM components leading to degenerative OA. Therefore, it is apparent that supplementing BMP2 at the initial stages of OA may have a significant inhibitory effect on the development of OA. Nonetheless, even with the high chondrogenic potency of BMP2, the biggest challenge lies in developing an efficient delivery system to counteract its short half life and rapid degradation in vivo.
Perlecan/HSPG2 is a heparan sulfate proteoglycan (HSPG) that represents an essential component of cartilage ECM. The NH2-terminal portion of perlecan (domain 1 or PlnD1) carrying HS chains specifically binds HBGFs through three consensus serine-glycine-aspartate (SGD) motifs and enhances their interaction with the cognate signal transducing receptor to stimulate biological processes. Thus, PlnD1 can act as a depot for BMP2 storage and controlled release, protect it from proteolytic degradation and potentiate its biological activity. Previous studies demonstrate that PlnD1 can be successfully used in vitro to modulate the chondrogenic bioactivity of BMP2. However, because of its own diffusion and susceptibility to degradation, PlnD1 only can be effectively used as a HBGF reservoir for in vivo cartilage repair if immobilized through conjugation to a larger biocompatible carrier.
A stable biomimetic HBGF delivery system has been developed by conjugating PlnD1 to hyaluronic acid (HA)-based microgels (PlnD1-HA). Previous in vitro study using PlnD1-HA microgels demonstrated a near zero-order release kinetic of BMP2 from this biomaterial along with enhanced chondrocytic differentiation with ECM production. HA is a natural component of articular cartilage that functions as a matrix organizer by interacting with other matrix molecules such as aggrecan. HA-based macromolecules also commonly are used in the clinic as viscosupplements to enhance joint mobility and provide temporary relief of knee pain by increasing the viscosity and elasticity of synovial fluid. However, HA alone does not promote the regeneration of cartilage ECM and is traditionally not administered in combination with active cartilage repair agents. Thus, increased physical activity after palliative injection of HA often results in long term adverse effects and accelerates disease progression.
Thus, there remains a need for an effective and safe delivery system for HBGFs to enhance chondrogenesis in subjects, especially those who have suffered and/or are predisposed to cartilage damage.